CAREER: Computational and Theoretical Investigation of Actomyosin Contraction Systems

职业：肌动球蛋白收缩系统的计算和理论研究

• 批准号: 2340865
• 负责人: Julio Belmonte
• 金额: $ 53.69万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2029-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2340865&HistoricalAwards=false
• 关键词: CAREER; Computational; Theoretical; Investigation; Actomyosin

The function and development of organisms depends on the incessant activities of its cells. As we growth from a small embryo, cells are constantly growing, dividing, migrating, changing shapes and pulling on each other. Even as adults, our cells continue these processes to maintain body functions and heal in response to injury. All these activities rely on the cells’ ability to generate and transmit forces. The actin cytoskeleton, a meshwork of small, dynamic filaments (actin) and molecular motors that exists inside each cell, is the main driver of force generation and propagation within cells and across tissues and organs.All cells need a functional actin cytoskeleton to maintain their shapes, divide into new cells and drive morphogenesis during development. Without an optimally functioning actin cytoskeleton, cells’ ability to migrate, differentiate, divide and respond to injury is compromised, leading to birth defects, cancers, fibrosis, immunodeficiencies, etc. To fully understand these processes, we need to first understand how the actin cytoskeleton works as a function of its components (motors, filaments and crosslinkers), and how it generates and transmits forces within and between cells. Elucidation of the actin cytoskeleton’s activities from a molecular (bottom up) view, is imperative in order to provide a mechanistic understanding of all its associated cell processes and provide new therapeutic targets related to cytoskeletal dysfunction.Experimental cell biology and in vitro studies have revealed many aspects of actin cytoskeleton contraction, such as the movement of molecular motors, the actin and motor organization underneath cell membranes (the cortex), and their role during cell division. However, many important questions that must be addressed are extremely difficult, if not impossible, to probe with experiments alone. These include: 1) What are the multiple mechanisms that the actin cytoskeleton use to contract?; 2) What makes one contraction mechanism dominant over the others?; 3) How much force can a network produce?; and 4) How do adjacent networks interact?Fortunately, there have been dramatic recent improvements in computer power and simulation methodologies that now allow us to conduct in silico, computational experiments that circumvent wet lab constraints, opening novel ways to probe and uncover hidden aspects of actin dynamics not previously accessible. This project takes advantage of these improvements with a novel, systematic series of theoretical and computational studies of cytoskeletal dynamics using state-of-the-art simulation techniques and new approaches developed in the Principal Investigator laboratory. This project is divided into two scientific tasks that leverage our group’s expertise in physics. The first aim is to model all three main actin contraction mechanisms (filament buckling, polarity sorting, and depolymerization end-tracking) and ask under which conditions each becomes dominant over the others and when synergistic and antagonistic effects arise. Results from this task will serve as a guide to determine the underlying contraction mechanism in different cells and the degree to which different perturbations would enhance or impart its function. In the second aim the Principal Investigator will investigate how much force actin networks can produce, sustain over time, and transmit to adjacent networks. Current studies focus mostly on contraction rates, which does not provide a sufficient picture for the long-term effects of actin contraction. This new approach will help fill the gap between the cytoskeleton’s internal dynamics and large-scale cell behaviors. In addition, the Principal Investigator will also implement an educational plan consisting activities targeted to different groups: (i) a summer workshop on modelling cytoskeletal systems opened for the whole scientific community; (ii) a special topics course on physics of the cytoskeletal for seniors and graduate students at North Carolina State University; and (iii) a K-12 outreach activity to teach STEM concepts using archery. These three interrelated tasks are designed to address fundamental questions of high relevance in the physics of living systems. Completion of these tasks will provide a solid theoretical foundation of the inner workings of the actin cytoskeleton and pave the way for realistic models of in vivo systems, allowing us to study actin-associated cellular processes and diseases from a mechanistic point of view.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

生物体的功能和发育取决于其细胞的持续活动，当我们从一个小胚胎开始生长时，细胞不断生长、分裂、迁移、改变形状并相互拉扯，即使在成年后，我们的细胞也会继续这些过程。所有这些活动都依赖于细胞产生和传递力的能力，肌动蛋白细胞骨架是存在于每个细胞内的由小型动态丝（肌动蛋白）和分子马达组成的网络。主要驱动力所有细胞都需要功能性肌动蛋白细胞骨架来维持其形状、分裂成新细胞并在发育过程中驱动形态发生。如果没有最佳功能的肌动蛋白细胞骨架，细胞就无法迁移、分化、分裂和生长。对损伤的反应受到损害，导致出生缺陷、癌症、纤维化、免疫缺陷等。为了充分理解这些过程，我们需要首先了解肌动蛋白细胞骨架如何作为其组件（马达、肌动蛋白细胞骨架的活性（丝和交联剂），以及它如何在细胞内和细胞间产生和传递力，必须从分子（自下而上）的角度阐明肌动蛋白细胞骨架的活动，以便提供对其所有相关细胞过程的机械理解并提供新的信息。与细胞骨架功能障碍相关的治疗靶点。实验细胞生物学和体外研究揭示了肌动蛋白细胞骨架收缩的许多方面，例如分子马达的运动、细胞下的肌动蛋白和运动组织然而，仅通过实验来探究许多必须解决的重要问题是极其困难的，甚至是不可能的，其中包括：1）肌动蛋白细胞骨架的多种机制是什么。 ; 2) 是什么使得一种收缩机制优于其他机制？; 3) 网络可以产生多大的力量？; 4) 相邻网络如何相互作用？现在允许的模拟方法我们在计算机上进行计算实验，规避湿实验室的限制，开辟新的方法来探索和揭示以前无法实现的肌动蛋白动力学的隐藏方面，该项目通过一系列新颖的、系统的细胞骨架理论和计算研究利用了这些改进。使用首席研究员实验室开发的最先进的模拟技术和新方法进行动力学研究。该项目分为两个利用我们小组的物理学专业知识的科学任务，第一个目标是对所有三种主要肌动蛋白收缩机制进行建模。灯丝屈曲、极性排序和解聚末端跟踪），并询问在什么条件下每种细胞相对于其他细胞占主导地位，以及何时出现协同效应和拮抗效应，该任务的结果将作为确定不同细胞中潜在收缩机制及其程度的指南。在第二个目标中，首席研究员将研究肌动蛋白网络可以产生、维持并传递到相邻网络的力量，目前的研究主要集中在收缩率上。图片为这种新方法将有助于填补细胞骨架的内部动力学和大规模细胞行为之间的差距。此外，首席研究员还将实施一项由针对不同群体的活动组成的教育计划。 ) 为整个科学界举办的细胞骨架系统建模夏季研讨会；(ii) 为北卡罗来纳州立大学高年级学生和研究生开设的细胞骨架物理学专题课程；以及 (iii) 开展 K-12 外展活动； STEM 概念使用这三个相互关联的任务旨在解决生命系统物理学中高度相关的基本问题，完成这些任务将为肌动蛋白细胞骨架的内部运作提供坚实的理论基础，并为体内的现实模型铺平道路。系统，使我们能够从机械的角度研究肌动蛋白相关的细胞过程和疾病。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。